The last few years have documented the expression of many different cytokines/growth factors in the female reproductive tract. In many cases their synthesis is regulated by the polypeptide and sex steroid hormones known to exert overall control of reproduction, suggesting that these growth factors are the local mediators of hormone action. This has been confirmed using null mutants in the cytokine/growth factor genes. Amongst the first growth factors to be studied was the mononuclear phagocytic growth factor, colony stimulating factor-1 (CSF-1), whose expression pattern, together with that of its receptor, in the ovary and uterus suggested roles in reproduction, in addition to those in regulating mononuclear phagocytic function. Our analysis of the CSF-1 nullizygous mice has confirmed these roles for CSF-1 in reproduction with major effects being on neuroendocrine function, ovulation and mammary gland development. Because in all null mouse mutants the gene product is ablated from conception, the effects of its absence in one cell type can have pleiotropic effects on other cell types. An important challenge therefore, is to identify unequivocally the effector cells for each individual phenotype. In this application we will use transgenic technology to spatially and temporally restore, or ablate, CSF-1 signaling to fully define the cell type specific mechanisms of CSF-1 action in female reproduction. Many of the growth factors/cytokines found in the female reproductive tract were originally characterized as hematopoietic cytokines. CSF-1 is one of these, being originally isolated as a macrophage growth factor. A significant gap in immunological knowledge is how infection is controlled at the utero-placental interface, while at the same time an immune reaction is not mounted against the allogenic fetus. The CSF-1 receptor is not only expressed in macrophages but also in trophoblast. Based upon our observations of acute susceptibility of CSF-1 nullizygous mice to placental infection with Listeria monocytogenes, we hypothesize that CSF-1 has an important immunological role during reproduction through the regulation of immune cytokine synthesis by the trophoblast. Our studies aim to identify the important cytokines and to restore CSF-1 signaling in trophoblast independently of other cell types and examine the effect of this on the immune response to L. monocytogenes in order to test this hypothesis. Furthermore, we will identify CSF-1 regulated cytokines in the placenta and use genetic means to ablate them to confirm their importance in controlling this infection. Since L. monocytogenes causes significant fetal morbidity and mortality during pregnancy in humans, such studies might also point to areas for therapeutic intervention in this infection during pregnancy.